NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding homer proteins

Guo N. Huang, David L Huso, Samuel Bouyain, Jianchen Tu, Kelly A. McCorkell, Michael J. May, Yuwen Zhu, Michael Lutz, Samuel Collins, Marlin Dehoff, Shin Kang, Katharine Whartenby, Jonathan Powell, Daniel J Leahy, Paul F. Worley

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

T cell receptor (TCR) and costimulatory receptor (CD28) signals cooperate in activating T cells, although understanding of how these pathways are themselves regulated is incomplete. We found that Homer2 and Homer3, members of the Homer family of cytoplasmic scaffolding proteins, are negative regulators of T cell activation. This is achieved through binding of nuclear factor of activated T cells (NFAT) and by competing with calcineurin. Homer-NFAT binding was also antagonized by active serine-threonine kinase AKT, thereby enhancing TCR signaling via calcineurin-dependent dephosphorylation of NFAT. This corresponded with changes in cytokine expression and an increase in effector-memory T cell populations in Homer-deficient mice, which also developed autoimmune-like pathology. These results demonstrate a further means by which costimulatory signals are regulated to control self-reactivity.

Original languageEnglish (US)
Pages (from-to)476-481
Number of pages6
JournalScience
Volume319
Issue number5862
DOIs
StatePublished - Jan 25 2008

ASJC Scopus subject areas

  • General

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